The induction of the human hepatic CYP2E1 gene by interleukin 4 is transcriptional and regulated by protein kinase C

Cytochrome P4502E1 (CYP2E1) plays a key role in the metabolism of numerous drug substrates, mostly in mammalian liver. Both the apoprotein and mRNA le vels are increased in response to interleukin 4 (IL-4) in primary human hep atocyte cultures. We developed a human hepatoma cell model that faithfully reproduces the responsiveness of the CYP2E1 gene to IL-4 at least in part t hrough transcriptional activation, upon treatment with 150 U/ml of IL-4. As expected, IL-4 induced tyrosine phosphorylation of the STAT6 transcription factor, an effect prevented by the tyrosine kinase inhibitor tyrphostin A2 5. However, this inhibitor as well as genistein (another inhibitor of tyros ine kinases) had no effect on the IL-4 induction of CYP2E1. Similarly, prot ein kinase A activators (forskolin and dibutyryl-cAMP) and inhibitor (H89) did not influence the response to IL-4. However, PKC inhibitors (H7 and cal phostin C) strongly blocked any induction of the gene, as well as the IL-4- dependent translocation of PKC zeta. Taken together, our results show that IL-4 coordinately induces CYP2E1 transcription, mRNA and apoprotein levels in human hepatoma cells in a PKC-dependent manner, potentially through the activity of the PKC zeta isoform.